The long-term objective of this research is to identify the biochemical lesion(s) responsible for cell damage following an ischemic episode. What the pathogenic event is, as well as where and when it occurs, has been the subject of some controversy. The fate of the tissue may be determined during ischemia, but there is also evidence that reintroduction of oxygen and glucose elicits a unique metabolic response, suggesting that the recovery process is not a mere reversal of ischemia-induced events. The observation that the entire population of CA 1 neurons in the anterior hippocampus die at 4 days of recirculation following 5 min of bilateral ischemia in the gerbil provides a reproducible response for investigating the biochemical events that precede cell death. The proposed experiments are designed to: 1) examine the effects of transient ischemia on long-term metabolic recovery in brain regions exhibiting different levels of susceptibility to ischemia, 2) test a number of current hypotheses concerning the pathomechanisms of ischemic cell death and delayed neuronal death and 3) further evaluate the neuroprotective effects of GABAergic agents. In these experiments in vivo, the levels of high-energy phosphates, glucose-related metabolites, cyclic nucleotides and certain amino acid neurotransmitters will be measured in the somal layer of the CA 1 and CA 3 region of the hippocampus and the cortex at various times of recirculation following 5 min of bilateral ischemia. The tissue samples weigh approximately 1 ug and microquantitative histochemical methods will be required to measure the metabolites in the pmole range. Finally, the loss of the CA 1 neurons at 4 days of reflow following 5 min of bilateral ischemia greatly increases the glia to neuron ratio in this region. This neuron-depleted area will be examined both during a secondary ischemia and recirculation to determine the contribution of a glial-enriched tissue to the ischemic response. A greater glial acidification during ischemia has been demonstrated, but the metabolic correlates in glia have not been examined. The importance of acid-base balance in glia may well explain the evolution of ischemic cell damage. The natural history of delayed neuronal death will be better described by these discrete measurements and it is anticipated that the information will serve as a temporal and biochemical guide for testing novel therapeutic approaches to the treatment of stroke.